BET inhibition-induced GSK3β feedback enhances lymphoma vulnerability to PI3K inhibitors Journal Article

Authors: Derenzini, E.; Mondello, P.; Erazo, T.; Portelinha, A.; Liu, Y.; Scallion, M.; Asgari, Z.; Philip, J.; Hilden, P.; Valli, D.; Rossi, A.; Djaballah, H.; Ouerfelli, O.; de Stanchina, E.; Seshan, V. E.; Hendrickson, R. C.; Younes, A.
Article Title: BET inhibition-induced GSK3β feedback enhances lymphoma vulnerability to PI3K inhibitors
Abstract: The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase β (GSK3β) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3β S9 inhibitory phosphorylation, resulting in increased β-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3β S9 phosphorylation levels and β-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3β S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3β regulation, providing a mechanistic rationale for combination strategies. In this study, Derenzini et al. demonstrate that BET inhibitors enhance lymphoma vulnerability to PI3K inhibitors by inducing GSK3β feedback in a MYC-dependent manner and by downregulating E2-ubiquitin conjugating enzymes, which further enhance the feedback. These data provide the rationale for combining BET and PI3K inhibitors in lymphoma therapy. © 2018 The Authors
Keywords: lymphoma; pi3k; myc; dlbcl; gsk3β; diffuse large b cell lymphoma; jq1; bet inhibitor
Journal Title: Cell Reports
Volume: 24
Issue: 8
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2018-08-21
Start Page: 2155
End Page: 2166
Language: English
DOI: 10.1016/j.celrep.2018.07.055
PROVIDER: scopus
PUBMED: 30134175
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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